[CANCER RESEARCH 28, 378-383, February 1968]
The Syndrome of Inappropriate Secretion of Antidiuretic Hormone:
A Case Report and Characterization of an Antidiuretic Hormone-like
Material Isolated from an Oat Cell Carcinoma of the Lung
H. S. Lipscomb,1C. Wilson, K. Retiene7 F. Matsen, and D. N. Ward
BayIor University College of Medicine, and M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77025
SUMMARY
This paper presents a report of a patient with the syndrome
of inappropriate secretion of antidiuretic hormone associated
with an oat cell carcinoma of the lung. Antidiuretic activity
was found on bioassay of plasma and tumor extracts. The
active material could be extracted from the tumor by procedures known to isolate the native human peptide, arginine
vasopressin. The material passed through a Sephadex G-25
column with a Ve/Vo ratio identical to that of vasopressin;
on counter-current distribution, the material possessed a partition coefficient identical to that of purified arginine vasopressin.
INTRODUCTION
It has long been known that neoplasms of endocrine tissues
are capable of elaborating excessive quantities of the hormone
normally produced by the endocrine organ. The clinical syndromes associated with such tumors are well recognized. Recently, a growing number of papers have described neoplasms
of nonendocrine tissues associated with endocrine disorders. The
syndromes associated with such neoplasms include Cushing's
syndrome, hyperthyroidism , hypercalcemia, hypoglycemia, erythrocytosis, atypical carcinoid syndrome, precocious puberty,
and inappropriate secretion of antidiuretic hormone. The subject of endocrine syndromes associated with malignant tumors
of nonendocrine origin has been extensively reviewed (7, 21,
3 2 , 33, 36). The hormonal substances have been partially
characterized and, in some cases, the evidence indicates that
the material produced by the tumor is identical to the naturally
occurring hormone; in other cases, the substance, although
biologically active, is structurally dissimilar to the natural
product.
The present report is that of the twenty-seventh patient
reported with the syndrome of inappropriate secretion of ADH
(antidiuretic hormone or vasopressin) associated with bronchogenic oat cell carcinoma and demonstrable plasma antidiuretic
activity (31). It is the first case in which gel filtration and
1 This study was supported in part by USPHS Grant AM-04122
and American Cancer Society Institutional Research Grant ACSIN-27-G-Project 1.
2 Supported by NATO postdoctoral fellowship.
Received June 12, 1967; accepted October 22, 1967.
378
cou~er-current distribution studies of the antidiuretic material
isolated from the tumor have been carried out.
CLINICAL HISTORY
A 61-year-old white man was admitted to Methodist Hospital
with a six-week history of intermittent epigastric pain, anorexia, malaise, a nine pound weight loss, and episodes of irrational behavior. His past and family history and review of
systems were noncontributory. He had smoked one pack of
cigarettes daily for more than thirty years. Physical examination upon admission was unremarkable. Hematologic studies
and urinalysis were within normal limits. Blood urea nitrogen,
total serum proteins, serum calcium, and serum phosphorus
were all normal. Bromsulphalein retention was 22% after 30
minutes, but other liver function tests were normal. Glucose
tolerance, intravenous pyelogram, and radiologic studies of the
upper and lower gastrointestinal tract showed no abnormalities.
Serum sodium was 112 mEq/liter, chloride 83 mEq/liter,
potassium 4.8 mEq/liter, and carbon dioxide combining power
23 mEq/liter. At that time serum osmolality was 234 mOsm/kg,
and urine osmolality was 659 mOsm/kg. The possibility of
inappropriate secretion of ADH was entertained.
Further studies revealed 24-hour urinary excretion of I7hydroxycorticosteroids at 5.5 mg and 17-ketosteroids at 6.2 mg.
A T-3 test was normal. Urine coproporphyrins, protoporphyrins, and uroporphyrins were normal. An EEG revealed only
diffuse slowing. Isotope studies demonstrated an increase of
total body water with elevation in both extracellular and intracellular fluid compartments with normal total body sodium.
Blood was drawn for determination of ADH activity.
A chest X-ray showed changes suggestive of carcinoma of
the lung. On bronchoscopy, a lesion of the right upper lobe
bronchus was biopsied, confirming the impression of bronchogenic carcinoma. The tumor was judged to be nonresectable,
and the hilus was irradiated with 700 roentgens. The tumor
decreased in size on X-ray, but the patient's condition deteriorated. When water intake was restricted to less than
100 ml daily, the serum sodium rose to 128 mEq/liter. The
urine continued to be hypertonic to the plasma. On a diet
containing 8.6 mEq of sodium daily, a 24-hour urine sample
contained 46 mEq of sodium, 51 mEq of potassium and 63 mEq
of chloride, with an osmolality of 553 mOsm/kg. The patient
developed a severe anemia and pancytopenia. Bone marrow
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I n a p p r o p r i a t e Secretion o] A n t i d i u r e t i c H o r m o n e
biopsy showed almost complete replacement by neoplastic cells.
Chemotherapy with eyclophosphamide and corticosteroids was
initiated with little clinical improvement. The patient expired
three months after the initial admission.
At autopsy, which was restricted to the thorax, a tumor
mass 1.5 X 2.5 cm was found in the right upper primary
bronchus 9 The t u m o r was of the undifferentiated small cell, or
oat cell, type. There were widespread metastases to both lungs
and throughout the mediastinum. Approximately 10 gm of the
tumor tissue was taken for biochemical and biologic studies.
MATERIALS A N D M E T H O D S
Bioassays. F m measurement of antidiuretic activity in both
plasma and t u m o r extracts, ethanol-blocked, water-loaded rats
were employed (12, 15). Because this is a difficult assay and
responses to standards v a r y among individual animals and in a
single animal during the test period, each test dose was bracketed
by arginine vasopressin standards. Responses were obtained in
some animals to as little as 10 /~U of USP Standard arginine
vasopressin.
The pithed-rat pressor assay was employed t o determine
pressor activity of tumor extracts (13) Consistent responses
could be obtained with as little as 0.5 m U of USP Standard
arginine vasopressin.
Extraction Procedures. The tumor tissue collected at autopsy
was minced and placed in chilled acetone. The partially defatted and dried residue was subjected to a modified K a m m
procedure (24). The material was first extracted directly into
200 ml of 0.5% acetic acid. The extraction mixture, with brisk
stirring, was heated to 90~ for 30 minutes, cooled, and filtered.
The procedure was repeated on the residue. The clear filtrates
were combined, concentrated, and lyophilized to obtain the
acetic acid-soluble portion which was assayed for ADH activity.
The acetic acid-soluble fraction was dissolved in 0.1 ~f pyridine acetate buffer at p i t 4.5. The insoluble portion was removed by eentrifugation, and the soluble portion was submitted
to molecular sieve filtration on Sephadex G-25 in a column
2 X 100 em with a flow rate of 37 ml per hour at 24~ (20).
The 600-ml effluent was collected in 4.5 ml fractions, and
0.5 ml aliquots were removed from every tenth fraction for
assay of antidiuretic activity.
The tubes containing ADH-like activity were pooled and
lyophilized. Counter-current distribution was done using 20
standard taper stoppered cylinders wired in sequence on a test
tube rack; each tube contained 1.5 ml per phase of the system
0.03 ~p-toluene sulfonic acid and 2-butanol (47). All transfers
were made manually for the upper phase transport to the adjoining tube at each distribution transfer step. After 20 transfers, 0.1 ml of the lower phase was analyzed for protein content by the Folin-Lowry reaction (34). Aliquots were also taken
for pressor assay after dilution with distilled water, neutralization of the sulfonie acid, lyophilization, and reconstitution with
distilled water.
Material from those tubes subjected to counter-current distribution containing pressor and A D H activity were combined
for a thioglyeollate inactivation study. The fractions were dissolved in 2.4 ml water; one-half was used as an untreated
control with the addition of 1.2 ml of water, and the other half
was treated with an equal volume of 0.1 ~ thioglycollate at
pH 7.6, a procedure which has been shown to inactivate arginine
vasopressin (3). Pressor activity was assayed at approximate!y
ten-minute intervals after the addition of thioglycollate.
RESULTS
Plasma A D H Activity. Injection of 0.1 and 0.2-ml samples
of plasma from the patient on two occasions in a single test
animal produced an antidiuretie response equivalent to that
produced by an equal volume of a standard solution containing
SEPHADEX
Dilute
HAr
Column:
Buffer,
oB
G-25
Extroct
of
Tumor
2 = I 0 0 cm
0.1 M
Pyridine Acetote
pH 4 . 5
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to
11:
~ 04
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o,z
-
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,
IO0
500
200
400
600
500
EFFLUENT
mI
Chart 1. Gel filtration of 1.05 gm of dilute acetic acid-soluble
material from an oat cell carcinoma of the lung. Solid line: FolinLowry reaction of 0.1 ml aliquots. Bar: fraction of effluent with
ADH activity. HAc, acetic acid.
~.2
i,
I.I
i ~.o
"~ o.9
~ 0.B
~ oz
~ o.6
N o.5
~ 0.4
~g o.3
O.2
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K =0.32
K=0.54
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II
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9~
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i
,: >, -\
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TUBE
9
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12
13
14
15
16
17
18
19
NUMBER
Chart 2. Counter-current distribution in 0.03 M p-toluene
sulfonic acid and 2-butanol of the fraction with ADH activity
from the gel filtration shown in Chart 2. Solid line : Folin-Lowry
reaction of 0.1 ml aliquots. Broken line: distribution of pressor
activity.
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379
H. S. Lipscomb, C. Wilson, K. Retiene, F. Matsen, and D. N. Ward
800 t~U/ml USP Standard arginine vasopressin. Injection of
equal volumes of plasma from normally hydrated control subjects failed to produce significant antidiuretic response in the
same animal.
Antidiuretic and Pressor Activity of Tumor Extracts. Pressor
assays of the acetic acid-soluble fraction which weighed 1.05 gm
yielded pressor activity equivalent to 0.2 mU of USP Standard
arginine vasopressin per milligram of the acetone-dried starting
material in four test animals. This is about one-thousandth the
concentration present in similar extracts of human posterior
pituitary tissue (4).
Aliquots from every tenth tube of the effluent collected from
the Sephadex gel filtration were subjected to assays for antidiuretic and pressor activity in four test animals. Significant
antidiuretic and pressor responses were present in the region
of 250-320 ml of the 600 ml effluent (Chart 1). The VJVo
ratio calculated at the midpoint of the band was 2.45, the Vo for
the column being 116 and the mean V~ 280. The value for pure
arginine vasopressin using this type of column and system has
been found to range between 2.15 and 2.7 (40).
The 189-mg fraction with pressor activity was submitted to
counter-current distribution to distinguish between arginine
and lysine vasopressin. Chart 2 shows the Folin-Lowry curve
for peptide concentration after twenty transfers, along with
rat pressor activity plotted against tube number. Pressor assays
in four different rats yielded identical results. Biologic activity
was localized to the area of Tube 7. The calculated partition
coefficient (K value) was found to be 0.54, and is identical to
the K value for purified arginine vasopressin (41, 47). The K
value of lysine vasopressin is 0.32 (41, 47).
Although at this point in our studies the active material was
far from pure, the quantity remaining was small and further
purification was not feasible. The material from Tubes 5
through 9 was pooled for a thioglycollate inactivation study.
After incubation with sodium thioglycollate for 90 minutes,
virtually all pressor activity had disappeared from the treated
fraction while activity in the control fraction remained unchanged.
We have estimated that the 10 grams of tumor tissue removed at autopsy contained antidiuretic hormone activity
equivalent to approximately 2 • 10-4 U of USP Standard arginine vasopressm per milligram of wet tissue. Thus, at the
onset of this study, the tissue received for analysis contained a
total activity of iess than 2 units or 5 /~g of vasopressin.
DISCUSSION
The structure of vasopressin from human pituitary glands
has been established (30). Vasopressin of porcine origin has
been found to differ from that of other animals in that it contains a lysine residue in place of arginine in the seven position
(16).
The syndrome of inappropriate secretion of ADH has been
described in association with a number of clinical conditions,
including myxedema (11, 39), acute intermittent porphyria
(35, 37), bronchogenic carcinoma (2, 6, 9, 28, 44), intracranial
disease (1, 17, 18), and tuberculosis (48), as well as in the
absence of any other apparent clinical abnormality (19, 22).
380
Clinically, this syndrome is characterized by persistent hyponatremia in the face of continued renal sodium excretion and
urine osmolality greater than that of plasma. There are no
signs of dehydration, and renal and adrenal function are normal. The extracellular fluid space is normal or only slightly
expanded. The electrolyte abnormalities do not respond to
sodium loading but, rather, are corrected by water restriction.
The term "inappropriate" secretion of ADH is used because
the persistence of ADH activity is not appropriate to the coexisting hypotonic plasma, a condition normally inhibiting
ADH release (26).
In the presence of a normal glomerular filtration rate, excretion of a hypertonic urine is presumptive evidence for the
presence of ADH. When normal subjects are given sustained
elevated doses of vasopressin along with abundant fluids, water
intoxication occurs. The signs and symptoms are similar to those
seen in patients with the syndrome of inappropriate secretion
of ADH with an apparent primary retention of water with
dilution of solutes and moderate increase in extracellular fluid
volume (23, 25, 29). An extreme increase in fluid volume is
prevented by increasing the renal excretion of sodium which
results in still further reduction of extracellular fluid osmolality.
Thus, constancy of volume is preserved at the expense of tonicity. The urinary sodium loss in these individuals probably
involves both an increase of glomerular filtration rate and a
decrease of aldosterone secretion in response to the expanded
plasma volume (5, 27, 20). On the other hand, when continuous vasopressin is given to normal subjects but fluid intake is
restricted, hyponatremia and urinary sodium loss do not occur
(23, 26, 27).
Hyponatremia in conjunction with bronchogenic oat cell carcinoma was first reported by Winkler and Crankshaw in 1938
(49)..Nearly 20 years elapsed before further note was taken of
this association. In 1957, Schwartz and his associates reported
two such cases and another in 1960 (42, 43, 44). A number
of endocrine and metabolic balance studies were carried out
that indicated that the abnormalities present could best be explained on the basis of sustained inappropriate ADH secretion.
Since that time, reports of the association of oat cell careinoma of the hmg and the syndrome of inappropriate secretion
of ADH have appeared with increasing frequency. In 1963,
Thorn and Transbf~l described a patient with this syndrome
whose urine contained large quantities of an antidiuretie substance (45). This material, excreted in 24 hours, possessed an
activity equivalent to approximately 3100 mU of arginine vasopressin. Incubation with thioglye.ollate destroyed 40% of this
activity, and treatment with trypsin destroyed all ant idiuretie
activity.
Shortly thereafter, a report of a ease by Amatruda et al.
appeared with careful balance studies demonstrating the charaeteristic abnormalities of the syndrome (2). Urinary aldosterone levels were normal. Injection of vasopressin produced no
increase in urine osmolality. Attempts to inhibit ADIt secretion
by vagal blockade and by the administration of ethanol and
ehlorpromazine had no effect on urine osmolality. At autopsy,
the primary tumor was extracted and assayed for antidiuretie
activity. The dried tumor contained antidiuretie activity equal
to approximately 70-350/xU arginine vasopressin per milligram.
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Inappropriate Secretion of Antidiuretic H o r m o n e
The characteristics of the antidiuresis in the bioassay of the
tumor extracts were similar to those of arginine vasopressin.
Biologic activity was destroyed by incubation with thioglycollate and by boiling with 0.1 N sodium hydroxide. The authors
suggested that the antidiuretie material might be vasopressin
or another polypeptide with antidiuretie activity.
Bower and his associates were the first to demonstrate elevated antidiuretic activity in the plasma of a patient with the
syndrome of inappropriate ADH secretion and bronchogenic
carcinoma (8, 9). Activity in plasma from the patient ranged
between 3 and 8/xU/ml, in contrast to normal subjects in whom
no activity was detected. No change in urine osmolality was
observed after administration of ethanol and of vasopressin
to the patient. Extracts of the primary tumor which had received local X - r a y therapy contained 0.1-1.0 ~ U / m g of antidiuretic activity, while extracts of the nonirradiated hepatic
metastases contained 6-8/~U/mg of antidiuretic activity. Selecrive destruction of the posterior pituitary gland by an isolated
metastasis was of interest in this patient. Assays were performed
in ethanol-blocked rats and in rats with permanent diabetes
insipidus produced by stereotaxically placed hypothalamic
lesions. Their results were identical in the two groups, indicating the material had intrinsic antidiuretic activity rather than
acting primarily as a stimulus for release of ADH.
De Sousa et aI. studied activity of an oat cell tumor extract
from a patient with the inappropriate A D H syndrome (14).
They found that antidiuretic, vasopressor, and milk-ejecting
activities of the substance were essentially in the same proportions as arginine vasopressin.
Recently, Utiger has described a patient with oat cell careinoma of the lung and inappropriate water retention in whom
the fluid and electrolyte abnormalities were corrected by excision of the tumor (46). Radioimmunoassay studies were
carried out on tumor extracts using labeled lysine vasopressin
and antiserum. The dose response curve of tumor extracts
closely paralleled that of a standard curve using arginine vasopressin. The tumor extracts contained activity equivalent to
8-427 t~U arginine vasopressin per milligram of wet tissue.
These studies would indicate that the tumor tissue contained
arginine vasopressin or a closely related peptide.
The present report describes a patient who had the clinical
hallmarks of the syndrome of inappropriate secretion of ADH.
Urine osmolality was consistently greater than that of serum.
Hyponatremia in the face of urinary sodium excretion was
responsive to water restriction but not salt loading. Determinations of total body water revealed increases in both extracellular and intracellular compartments in conjunction with
normal total body sodium. Renal and adrenal function were
intact. Tests for porphyria and hypothyroidism were negative.
A chest X-ray suggested carcinoma of the lung, and an oat cell
carcinoma was found on biopsy and on postmortem examination. Bioassays of plasma performed before death revealed
excessive antidiuretic activity. Crude extracts of the tumor
contained pressor and antidiuretic activity. Activity was destroyed by treatment with thioglycollate, suggesting the presence of a disulfide bond. The material containing this activity
could be extracted by the procedure used to isolate arginine
vasopressin from the neurohypophysis. The active fraction
passed through a Sephadex G-25 column with a V~/Vo ratio
identical to that of vasopressin, indicating residence of activity
in a molecule with physical dimensions and molecular configuration similar to those of vasopressin and oxytocin. When
subjected to counter-current distribution i n p-toluene sulfonic
acid and 2-butanol, the active material possessed a partition
coefficient identical to that of purified arginine vasopressin and
differing significantly from that of lysine vasopressin.
A number of mechanisms might be postulated to explain
how the tumor might be responsible for the induction of a
sustained inappropriate secretion of ADH. The theory most
widely accepted at the present postulates that the tumor is the
site of de novo synthesis of an ADH-like substance. The possibility that the ADH-like material in the tumor was synthesized
elsewhere and trapped in the tumor tissue cannot be ruled out.
However, if this were the case, one nmst postulate some protective m~.~hanism for the stabilization of vasopressin in the
tmnor, for vasopressin in the circulation is normally quickly
metabolized and has not been shown to be stored in significant
quantities in tissues other than the hypothalamus and posterior
pituitary.
We believe the most reasonable interpretation of our results
and those of others is that. the tumor itself contains the genetic
information for the synthesis of arginine vasopressin. This biosynthesis is not controlled by the usual regulating mechanisms,
and abnormally high and sustained levels of vasopressin are
released into the circulation to produce the clinical manifestations of this syndrome.
Although neoplastic transformation of tissue has t)een characterized classically by extensive dedifferentiation, iu these
cases of humoral syndromes associnted with tumors of nonendocrine tissues, neoplasia results in the production of r~-~ther
complex peptide hormones ordinarily considered highly specific
to endocrine organs. This apparent discrepancy mt~y be accounted for if the assumption is made that all cells have the
same genetic information coded on an identical complement
of D N A (32, 33). In the process of their dedifferentiation
these neoplastic cells may have lost a genetic repressor mechanism with the consequent unmasking of genetic information
normally not expressed. Thus, these rather unusual syndromes
provide a compelling link between molecular biology and
clinicaI medicine.
ACKNOWLEDGMENTS
W e thank Dr. R . . 4 . Johnston, Jr., who first brought this patient to our attention and Dr. Philip C. Johnson, who performed
the isotope determinations of body water compartments.
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F E B R U A R Y 1968
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383
The Syndrome of Inappropriate Secretion of Antidiuretic
Hormone: A Case Report and Characterization of an
Antidiuretic Hormone-like Material Isolated from an Oat Cell
Carcinoma of the Lung
H. S. Lipscomb, C. Wilson, K. Retiene, et al.
Cancer Res 1968;28:378-383.
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